Reproductive hormones have several protective effects on the brain, such as promoting cholinergic activity, reducing neuronal loss, and stimulating axonal sprouting and dendritic spine formation. In this application, it is hypothesized that reproductive events characterized by significant hormonal fluctuation (such as pregnancy and the menopausal transition) are associated with measurable decreases in cognition, and that multiple periods of estrogen depletion increases the risk of cognitive decline and dementia in later life. The overall aim of this Mentored Patient-Oriented Research Career Development Award (K23) is to lay the foundation for a programmatic approach to the study of hormones and cognition in women across the lifespan and to facilitate the candidate's development into an independent clinical neuroscience researcher. The candidate has extensive training and research experience in the neuropsychology of aging, dementia, and perimenopause and clinical trial methodology. The training program focuses on increasing knowledge and expertise in additional fields critical to this program of study: behavioral neuroscience, endocrinology, epidemiology, and statistics. The research proposal aims to clarify how hormonal changes during critical periods in the female reproductive life cycle might increase the risk of cognitive decline and Alzheimer's disease in later life and to develop a working hypothesis of how and when to intervene with experimental therapies aimed at preventing or limiting this outcome. The specific aims of the research plan are to: 1) determine if pregnancy is associated with measurable cognitive declines and if such declines ameliorate in the postpartum period, and 2) determine if the menopausal transition (MT) is associated with subjective and objective cognitive declines that ameliorate in menopause. Secondary aims are to determine the risk factors of cognitive impairment in the MT and to determine if cognitive impairments during the MT are predictive of age-related cognitive decline. PUBLIC HEALTH RELEVANCE: The results of these studies will lead to a greater understanding of hormonal effects on cognition throughout a woman's lifespan, with a particular emphasis on cognitive aging and risk of dementia. Further, they will clarify the trajectory of cognitive declines during reproductive events such as pregnancy and the menopausal transition, and may reveal risk factors for cognitive impairment during these events.